The female Anopheles gambiae mosquito is an extremely efficient vector for the malarial parasite Plasmodium falciparum and transmits this deadly disease to nearly 500 million people, causing nearly 750,000 deaths every year. Since the mosquito relies primarily on the sense of smell to find a human host, the olfactory system is a prime target for development of strategies to disrupt contact between mosquitoes and humans. Current methods of control that exploit the mosquito olfactory system such as repellents applied to the skin like DEET and CO2-traps are not useful for the population at risk due to high costs, inconvenience of direct skin applications, and bulk. The goal of this proposal is to identify affordable, convenient, and safe odor-based applications that can be used in small quantities to protect a spatial area such as an abode from Anopheles mosquitoes, and design low-cost lures for traps. One of the primary cues that mosquitoes use from a distance is CO2 present in exhaled breath. As the mosquito navigates closer using the CO2 plumes, it is also thought to be attracted to skin and sweat associated odors. In this proposal we focus on the CO2-sensing neuron of Anopheles gambiae as a target for development of odor-mediated behavior disruption strategies. For this purpose we have developed an array of powerful technologies that involve neurophysiology, chemical- informatics, and behavioral analysis. First, we plan to investigate a novel observation that the CO2-sensing neuron is also involved in detecting human-skin odorants, presumably causing close-range attraction. Since little is understood about attraction towards skin, we expect our analyses to reveal mechanisms underlying this important behavioral process. Second, we plan to identify odorants that can mimic the olfactory activity of CO2, and test their utility in acting as efficient lures for traps.And third, we propose to identify odorants that can block detection of CO2 by either inhibiting the CO2-sensing neuron, or by ultra-prolonged activation of the neuron. These CO2-detection masking odors will be tested for the ability to protect a spatial area, such as a small abode, from host-seeking Anopheles mosquitoes. Successful completion of this proposal will provide safe and affordable odorants that can reduce contact between humans and Anopheles gambiae mosquitoes.